tbuckley/cabot-search huggingface dataset:
TABLET: Relative bioavailability and bioequivalence study of niraparib tablets and capsules in patients with advanced solid tumors.
Authors: Gerald Steven Falchook, Amita Patnaik, Manish Sharma, R. Donald Harvey, Erika P. Hamilton, Navid Hafez, Trisha M. Wise-Draper, Minal A. Barve, Manish R. Patel, Afshin Dowlati, Debra L. Richardson, Christina Faltermeier, Reggie Ewesuedo, Michelle Kneissl, Elizabeth Potocka
Journal: Journal of Clinical Oncology (2023)

e17603 Background: Niraparib is a poly (ADP-ribose) polymerase inhibitor, approved as a maintenance treatment (tx) for patients (pts) with advanced ovarian cancer and under investigation in solid tumors, available in 100 mg capsules (starting dose: 200 or 300 mg/day). Compared with capsules, tablets have improved stability in hot and humid conditions. This study assessed the relative bioavailability (BA; Stage 1 [S1]) and bioequivalence (BE; Stage 2 [S2]) between niraparib tablets and capsules. Methods: This was a US, open-label, multicenter, single-cohort, randomized-sequence study with an optional extension phase. Eligible pts were ≥18 years, had histologically/cytologically confirmed advanced solid tumors (metastatic or local), disease progression despite standard therapy (if available), and ECOG performance scores of 0–2. Pts were dosed 1x300 mg tablet or 3x100 mg capsules then crossed over to the other tx after full washout. Pharmacokinetic (PK) parameters were assessed up to 168 hours post-niraparib dose; safety was assessed throughout and for 30 days after last dose (90 days for serious adverse events). A comparison of the log-transformed PK parameters (maximum observed plasma concentration [C max ], area under the plasma concentration–time curve from time 0 to time of the last quantifiable concentration [AUC 0–t ] and from time 0 extrapolated to infinity [AUC 0– ∞ ]) was carried out to evaluate the formulations using a linear mixed-effects model with fixed effects for sequence, period, and tx and random effect for pt nested within sequence. Results: Pts in both stages completed study drug and washout/PK periods and had sufficient PK samples to estimate PK parameters in both periods. In S1 (n=29), a comparable BA performance of both formulations was demonstrated; the 90% confidence intervals (CI) of the geometric least square means (LSM) for C max , AUC 0–t , and AUC 0– ∞ for tablet/capsule were within prespecified 0.80–1.25 limits (intra-pt variability: 12.4–21.9%). An initial 7-day washout period between PK assessments was extended to 14 days in S2 due to significant carryover reported in 6 pts in S1. In S2 (n=108), niraparib PK characteristics were similar following dosing with tablet or capsule (Table); LSM ratios of the key parameters were close to unity and 90% CI for the ratio of C max , AUC 0 –t , and AUC 0 –∞ were within prespecified 0.80–1.25 limits required to demonstrate BE. No new safety signals were reported. Conclusions: Both niraparib formulations were bioequivalent and can be used interchangeably. Editorial support was provided by Fishawack Health, funded by GSK. Clinical trial information: NCT03329001 . [Table: see text]
Effect of hypomethylating agent (HMA) exposure on survival of secondary acute myeloid leukemia (sAML) from myelodysplastic syndrome (MDS).
Authors: Diego Andres Adrianzen Herrera, Andrew Sparks, Akshee Batra, Neil A. Zakai
Journal: Journal of Clinical Oncology (2023)

e19076 Background: AML arising from previously treated myeloid neoplasm (tsAML) is considered a distinct category of sAML less responsive to therapy. AML from MDS (MDS-sAML) formerly treated with HMA is the most common entity in this category but has not been independently studied. We determined the impact of prior HMA therapy on MDS-sAML survival. Methods: Patients (pts) with MDS were identified in SEER-Medicare 2007-2017 by ICD-O-3 histology codes. MDS-sAML was confirmed by at least 2 AML ICD codes. Established algorithms were used to define MDS risk group, Charlson comorbid index (CCI), transfusion dependence and HMA therapy. We used logistic regression to test factors associated with HMA therapy before transformation, and multivariable Cox regression with propensity score matching (PSM) for survival analysis after transformation. Results: We included 1,871 pts with MDS-sAML, of which 1,151 (61.5%) received at least 1 HMA cycle before AML transformation and 826 (44.1%) had sustained HMA therapy (4 or more cycles). Preceding MDS was of low, intermediate, and high risk in 6.2%, 61.9%, and 31.9% pts, respectively. Younger age (odds ratio [OR] = 1.6, 95% confidence interval [95 CI]: 1.3-1.9), lower CI (OR = 1.4, 95 CI: 1.2-1.5), higher MDS risk (OR = 2.3, 95 CI: 2.3-2.8), and RBC (OR = 1.3, 95 CI: 1.2-1.5) and platelet transfusion dependence (OR = 3.4, 95 CI: 2.8-4.0), were associated with pre-AML HMA use (all respective p &lt; 0.05). Median OS after AML transformation was 3.3 months and was longer in pts previously treated with HMA, particularly ≥4 cycles (4 vs 2 months, p &lt; 0.01). The 1:1 matched HMA and non-HMA groups were similar for all variables listed in the table. In the PSM cohort, prior HMA therapy was associated with 22% lower hazard of death in MDS-sAML (hazard ratio [HR] = 0.78, 95 CI: 0.7-0.88, p &lt; 0.01). Traditional Cox regression adjusted for age, sex, race, MDS risk, CCI, RBC and platelet transfusion dependence, confirmed these results (HR = 0.76, 95 CI: 0.68-0.84, p &lt; 0.01). The point estimate of the association of HMA therapy with lower risk of death was lower in pts who received ≥4 cycles (HR = 0.62, 95 CI: 0.56-0.69, p &lt; 0.01). Conclusions: Real-world survival of MDS-sAML pts is dismal but HMA exposure preceding AML transformation is associated with longer survival. Further studies are needed to determine whether this reflects the impact of HMA on subsequent AML biology or residual confounding. [Table: see text]
Sexual orientation and gender identity data collection among NCI community oncology research program (NCORP) practices: A 5-year landscape update.
Authors: Elizabeth Jane Cathcart-Rake, Aminah Jatoi, Emily Van Meter Dressler, Carol A Kittel, Kathryn E. Weaver, Chandylen L Nightingale, Heather B. Neuman, Charles Stewart Kamen
Journal: Journal of Clinical Oncology (2023)

6548 Background: National organizations (ASCO, ACS, ACCR) have advocated for routine collection of sexual orientation and gender identity (SOGI) in cancer clinics to advance cancer health equity. In 2017, only 24% of NCI Community Oncology Research Program (NCORP) practices collected sexual orientation (SO) data, while 10% collected gender identity (GI) data; recent progress in collection is unknown. Methods: In 2022, NCORP practices again completed a Landscape Assessment to assess research capacity (funding support from 2UG1CA189824) and were asked whether they routinely collect SOGI data in the electronic health record (EHR). The proportions of practices reporting collection of SO and/or GI data and population level differences over time were calculated using Fisher’s exact tests. Univariate associations between SOGI data collection and site-related variables were evaluated using logistic regression; significant associations were then tested in separate multivariate logistic regression models. Results: 271 practices responded to the Landscape Assessment; 42% (114) reported that they routinely collect SO data, 58% (157) reported that they collect GI data; both were significantly higher than 2017 (p&lt;0.001). Compared to other regions, practices in Northeastern states were significantly more likely to report collecting GI, but not SO. Practices with higher proportions of White patients were also more likely to collect GI (p &lt; 0.001). Practices with community outreach staff were more likely to collect SO (Table 1). There were no significant differences in SOGI collection by Medicaid/Medicare patients, new cancer cases per year, or practice ownership. In both 2017 and 2022, sites in Southern states were less likely to collect GI than sites in other regions. Conclusions: Progress was made in SOGI collection between 2017 and 2022, but fewer than half of NCORP sites routinely collect SOGI data, in spite of national guidelines. Further examination of the cultural context of SOGI collection could inform efforts to improve data collection in the South and other regions. The lack of data on sexual and gender minority patients in the EHR contributes to health inequity and deficiencies in patient-centric care. [Table: see text]
Incidence of cardiac events in patients with MDS or AML receiving azacitidine or decitabine within a large community health system.
Authors: Noor Naffakh, Michael Williams, Priyam Patel, Rachel Pedersen, Michael Peterson, Anthony DeFranco, Stephen Medlin, Sherjeel Sana, Zartash Gul
Journal: Journal of Clinical Oncology (2023)

e19074 Background: Hypomethylating agents (HMA) such as decitabine and azacitidine are frontline therapies for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Limited data exist on subsequent cardiovascular (CV) events. Johnson et al. reported 170 patients receiving HMA + venetoclax with a CV event rate of 20%. Aims: To investigate the incidence of CV events in patients receiving HMA. Methods: We analyzed adult AML and MDS patients with &gt; 1 dose of azacitidine or decitabine from 1/2018-12/2020. New CV events were defined as new atrial fibrillation, acute coronary syndrome, cardiomyopathy, congestive heart failure, myocarditis, or pericarditis. Competing risks regression identified baseline predictors associated with time to first CV event while accounting for the competing event of death. Results: 94 patients with no CV history were evaluated which consisted of a mean age 69 +/- 12 years and 50% male. 56% had MDS and 44% AML. Patients with BMI ≥ 30 accounted for 38.3% of the sample. 44 (47%) patients had baseline echocardiogram assessments prior to initiation of HMA with EF of 61+/- 8%; 57 (61%) had a documented prescription of beta-blocker, ACE-I, or ARB at time of HMA initiation. In the 94 patients, 16 new cardiac events occurred. Median survival after therapy initiation was 14.8 months. In a competing risks univariate analysis, lower prior EF (after adjusting for no EF performed) and absence of pre-chemotherapy beta-blocker, ACE-I, or ARB were significantly associated with having a new cardiac event post chemotherapy start (hazard ratio per 5-unit decrease = 1.62 (1.33-1.99), p&lt;0.01 and HR=2.89 (1.08-7.77), p=0.03, respectively). Baseline BMI did not affect risk of a new CV event on HMA therapy (HR per 5 units=1.08 (0.78-1.50), p=0.63). Total HMA dose did not show significance as a predictor for CV events (HR=0.99 (0.987-1.009), p=0.72). Conclusions: We observed a CV event incidence of 19% at 3 years after the start of HMAs. Among patients receiving HMA chemotherapy, those with a lower baseline EF and those not on beta-blocker, ACE-I or ARB therapy prior to initiation of HMA had a higher incidence of cardiotoxicity. Neither pre-HMA BMI nor total HMA dose received appeared to predict risk for CV events. Further research is warranted evaluating the association between HMAs and cardiotoxicity. [Table: see text]
Cancer survival (SURVCANCER BRAZIL): Analysis of 132,621 cases from 19 hospital-based registries in southernmost Brazilian state comparing public and private insurance.
Authors: Juliana Giacomazzi, Fernando Cotait Maluf, Sheila Schuch Ferreira, Silvana Schneider, Rafael Jose Vargas Alves, Rodrigo Ughini Villarroel, Christina Pimentel Oppermann, Sandra Helena Comassetto Barros, Roberta Pozza, Marina Ractz Bueno, Gustavo Zerwes, Silvia Saueressig, Adriana Elisa Wilk, Rafael Armando Seewald, Rita De Cassia Costamilan, Bianca Tabajara Weiss, Marcelo Capra, Patricia Klarmann Ziegelmann
Journal: Journal of Clinical Oncology (2023)

6632 Background: Brazilian data for cancer survival are scarce. Therefore, we aimed to describe the 5-year overall survival (OS) of individuals with public and private insurance from Rio Grande do Sul/RS (Brazil) diagnosed with the 17 most incident tumors in the country. Methods: Data from 19 of the 27 hospital-based cancer registries from RS were integrated with the Brazilian Information System data. Individuals with confirmed cancer diagnoses between 2005-2017 were included. Passive follow-up time was calculated as the difference between diagnosis and death (from any cause) or censure date. Survival was estimated by Kaplan-Meier method. Comparison between the survival of individuals assisted by public or private insurance was evaluated using hazard ratios (HR) estimated by multivariate Frailty and Cox regression models with adjustments for age, sex, and economic status. Results: 5-year OS was higher for patients with private health insurance for 13 of the 17 cancers studied. Conclusions: The survival trends among cancer patients assisted by public and private health insurance systems reveal vast differences that may be likely attributable to differences in access to early diagnosis and optimum treatment. We hope our results will help government officials understand that ongoing cancer survival surveillance is an indispensable source of information and a key policy tool for public health decisions. [Table: see text]
Real-world behavioral restrictional practices of cancer patients (pts).
Authors: Eliya Shachar, Noy Moisa, Shira Peleg-Hasson, Tamar Safra, Ido Wolf, Daniel A. Vorobiof
Journal: Journal of Clinical Oncology (2023)

6592 Background: Quality of life (QoL) assessments do not measure pts’ ability to maintain normal daily activities during cancer therapy. Misbeliefs might promote avoidance of activities perceived as dangerous, compromising pts QoL. We examined the daily practices of actively treated pts with cancer. Methods: A locally validated questionnaire at the Tel-Aviv Sourasky Oncology Division was distributed internationally using the Belong.life social and professional digital health platform. We examined real-world pts reported practices, provided voluntarily and anonymously. The survey consisted of 15 questions, including demographic, clinical, behavioral parameters and sources guiding and supporting pts practices. Independent clinical and demographic variables were analyzed. Statistical analysis was performed, and a multivariate logistic regression was conducted to identify factors predicting restrictive behaviors. Results: The study population comprised 1,395 pts receiving active cancer therapy, reporting their outcomes from the Belong digital platform. Most respondents were from the United States (1082, 77.70%) and Israel (223, 16%), over the age of 40 (1309,93.8%),and female (987, 70.75%). Most common tumor types were breast (394,28.24%) and gastrointestinal cancers (199,14.26%). The majority of pts (1,005,72.88%) reported on at least 1 adopted limitation in daily activities, and 305 (21.86%) maintained more than half of these constraints. Daily life restrictions included avoiding sun exposure (779, 57.83%), international travel (417, 33.33%), indoor public places (malls, etc) (431, 33.13%), hair dyeing (271, 22.72%), domestic tourism (284, 21.93%), contact with friends and family (231, 17.69%), children and grandchildren (202, 16.33%), outdoor public spaces (190, 14.62%), and contact with pets (135, 10.41%). Multiple sources were implicated by the pts as guiding their behavior, with the most common being health-care professionals (951, 65.95%), followed by both non-medical authorities and health-care team (320, 22.19%), and non-medical advisors, including internet, pts forums, partners, friends, and family (171, 11.86%) Pts who maintained strict (≥50% of the limitations) and less strict restrictions, demonstrated no significant association between country of origin (p = 0.118), and education level (p = 0.3591). A significant association was noted between younger age (p = 0.0014), female sex (p = 0.0141) and primary cancer site (p &lt; 0.0001), and the adoption of strict restrictions. Conclusions: The majority of pts reported compromised daily activities, which are likely attributed to misconceptions about therapy and disease, deleteriously impacting QoL, therefore, impeding their ability to continue to conduct a complete and meaningful life. These findings require development of tools examining patients’ real-daily life activity as an additional endpoint in clinical trials.
Practice- and provider-level inequities in next-generation sequencing (NGS) testing by race/ethnicity for patients (pts) with advanced non-small cell lung cancer (aNSCLC) treated in the community setting.
Authors: Gregory A. Vidal, Neha Jain, Aaron Fisher, Daniel Sheinson, Katherine T Lofgren, Esprit Ma, Elaine Yu, Leah Comment, Rebecca A. Miksad, Davey B. Daniel
Journal: Journal of Clinical Oncology (2023)

6508 Background: Inequities in NGS testing in pts with aNSCLC are well documented. Here, we examined elements of total inequity in NGS testing for pts with aNSCLC treated in the US community setting, in terms of within and between inequities at the practice and provider level. Methods: Using the nationwide, deidentified, electronic health record–derived Flatiron Health database, we studied pts with aNSCLC diagnosed in April 2018 or later and treated in the community setting. Testing quality was defined as an NGS result reported ≤60 days after advanced diagnosis. Total-practice inequity was the average percentage-point (pp) difference in the rate of testing quality for non-Latinx Black or Latinx pts compared with non-Latinx white pts. Within-practice inequity was the average pp difference in testing rates at a practice weighted by overall practice enrollment. Between-practice inequity was the covariance between a practice's overall testing rate and the extent of practice-level racial/ethnic underrepresentation. We estimated these inequities at the practice and provider levels using a Bayesian approach. Results: Our study included a total of 12,045 pts (9,981 non-Latinx white, 1,528 non-Latinx Black, and 536 Latinx pts). Both within- and between-practice inequities contributed to total inequity in NGS testing for non-Latinx Black and Latinx pts compared with non-Latinx white pts (Table). For non-Latinx Black pts, between-practice inequities were estimated as 57% (3.77 pp/6.56 pp) of the total inequity in NGS testing; for Latinx pts, the contribution of between-practice inequity was 39% (3.13 pp/8.01 pp). At the provider level, between-provider inequities were the dominant contributor to total inequity in NGS testing for both non-Latinx Black and Latinx pts, accounting for 86% (5.88 pp/6.87 pp) of total provider-level inequity for non-Latinx Black pts and 64% (5.36 pp/8.43 pp) for Latinx pts. Conclusions: Inequities within and between practices, as well as between providers, are meaningful contributors to total inequity in NGS testing. Additional healthcare equity initiatives are needed to identify potential causes for lagging practices/providers to address inequities in NGS testing. [Table: see text]
A phase Ib/II, open-label, multicenter study to evaluate the safety, efficacy, and pharmacokinetics/pharmacodynamics of αvβ3/5 integrin and neuropilin-1 targeting peptide LSTA1 in patients with metastatic pancreatic ductal adenocarcinoma.
Authors: Jianming Xu, Zuoxing Niu, Yuxian Bai, Wensheng Qiu, Jiuwei Cui, Xiujuan Qu, Zheng Wu, Yong Zha, Tao Zhang, Wei Cheng, Cuicui Han, Meimei Si, Lingyan Li, Xiaoyan Kang
Journal: Journal of Clinical Oncology (2023)

e16290 Background: LSTA1, formerly known as CEND-1, is a novel cyclic peptide which selectively binds to αv/β3 and β5 integrins, which are upregulated in solid tumors, where it undergoes protease cleavage producing a C-end rule peptide fragment (CendR) that selectively binds to and activates neuropilin-1 (NRP1). Once CendR binds NRP1, the CendR pathway is activated, leading to increased vascular permeability of tumors resulting in increased drug delivery and tumor accumulation of co-administered chemotherapeutic agents. Here we report the safety and efficacy results from a Phase Ib/II, multicenter study of LSTA1 plus (SoC) gemcitabine and locally produced nab-paclitaxel in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). Methods: The study included a 7-day safety run-in and dose expansion/extension parts. Previously untreated patients with histologically confirmed mPDAC and ≥1 target lesion were treated with systemic chemotherapy and received LSTA1 (1.6 mg/kg or 3.2 mg/kg), gemcitabine (1000 mg/m²) and nab-paclitaxel (125 mg/m 2 ) on days 1, 8, 15, of each 28-day treatment cycle. LSTA1 alone was given during run-in to observe PK/PD. Treatment continued until disease progression or other discontinuation events. The primary endpoints were safety and preliminary efficacy. Results: As of 30 Nov 2022, 38 patients were enrolled at 10 sites in China (12 at 1.6 mg/kg; 26 at 3.2mg/kg). The median follow-up time was 6.28 months. 37 (97.4%) patients experienced TEAEs and 31 (81.6%) patients experienced grade≥3 TEAEs. The most common TEAEs were hematologic toxicity related to chemotherapy. The ORR was 42.9% (15/35) and DCR was 82.9% (29/35). The ORR in 1.6 mg/kg and 3.2 mg/kg groups was 45.5% and 41.7%, respectively. The mPFS in 1.6 mg/kg and 3.2 mg/kg groups was 7.43 months (95% CI: 0.59-NE) and 5.75 months (95% CI: 3.25-7.46) respectively. mOS was not reached. NRP1 expression levels were tested at baseline; six of whom had expression ≥40%. Of those, 4 had PRs and 2 had SD (ORR=66.7%; DCR=100%). The mPFS was 7.5 months. Conclusions: LSTA1 combined with SoC showed an acceptable safety profile in patients with mPDAC. Compared with historical SoC data, LSTA1 plus SoC numerically improved ORR and PFS. Higher NRP1 expression is associated with better ORR and PFS, suggesting NRP1 may be a potential biomarker of LSTA1 plus chemotherapy for mPDAC treatment. Further study is ongoing. Clinical trial information: NCT05052567 .
Breaking primary checkpoint inhibitor resistance: Interim analysis of a multicenter phase II study by intermittent application of an alkylating agent among patients with metastatic melanoma.
Authors: Lucie Heinzerling, Sebastian Haferkamp, Bastian Schilling, Carola Berking, Ed Geissler, Florian Zeman
Journal: Journal of Clinical Oncology (2023)

9544 Background: Patients with BRAF wildtype (wt) metastatic melanoma with primary resistance to immune checkpoint inhibitors (ICI) have a dismal prognosis. Chemotherapy has been shown to induce mutations, alter the tumor microenvironment as well as the microbiome, and modulate the immune system. This prospective phase II trial investigates whether two applications of an alkylating agent (dacarbazine/DTIC) can render ICI non-responsive patients with metastatic melanoma responsive to the same checkpoint inhibitor regime. Methods: The PROMIT trial (NCT04225390) targets patients with histologically confirmed BRAFwt metastatic melanoma showing primary resistance to ICI therapy. Applying an optimal two-step design, the uninteresting responder rate was set to 5% with an expected rate of 20%. Response is defined as complete or partial response by week 14 according to RECIST 1.1. Design foresaw 29 assessable patients at first step and 38 patients overall (alpha one-sided 5%, 90% power).After showing primary resistance to ICI, patients received 2 doses of DTIC (850 mg/m 2 i.v.) on days 1 and 21, and were subsequently re-exposed to the same ICI therapy they had previously shown resistance to. Results: In total, 38 patients were screened at 4 skin cancer centers. Interim analysis was performed after 29 patients who had received at least one ICI re-exposure were assessable for efficacy. Overall response rate was 24% (90%CI 12-41%) with 7 out of 29 patients showing a partial response; disease control rate was 38%. Application was well tolerated with 16% grade 3 or more adverse events and no new safety signals. Conclusions: Interim analyses results indicate that this approach of a short-term chemotherapy can break resistance in a subgroup of patients and allows us to continue the phase II trial to assess relevance of this treatment approach for metastatic melanoma. Enrolment is ongoing. Clinical trial information: NCT04225390 .